Injection Device with Compression Spring for Engaging Ratchet Elements, for Biasing an Actuation Button, and for Biasing a Locking Element into a Dose Setting Mode

ABSTRACT

The present invention is generally directed to an injection device for selecting and dispensing a number of user variable doses of a medicament. The injection device comprises a housing ( 10 ) having a longitudinal axis (I), a dose setting member ( 60; 80 ) rotatable relative to the housing ( 10 ) during dose setting, a drive member ( 40 ) which is rotationally constrained to the housing ( 10 ) in a first dose setting mode and which is rotatable relative to the housing ( 10 ) in a second dose dispensing mode, a locking element ( 100 ) which is permanently rotationally constrained to the housing ( 10 ) and movable relative to the housing ( 10 ) in a direction parallel to the longitudinal axis (I) between a first dose setting position and a second dose dispensing position, an actuation button ( 70 ) movable relative to the housing ( 10 ) in a direction parallel to the longitudinal axis (I) between a first dose setting position and a second dose dispensing position for switching the injection device between the first dose setting mode and the second dose dispensing mode, a ratchet ( 42, 120 ) for transmitting torque from the dose setting member ( 60 ) to the drive member ( 40 ) during dose dispensing and allowing relative rotational movement between the dose setting member ( 60 ) and the drive member ( 40 ) during dose setting, the ratchet ( 42, 120 ) comprising first ratchet features ( 43 ) rotationally constrained to the driver ( 40 ) and second ratchet features ( 121 ) rotationally constrained to the dose setting member ( 60 ), and a spring ( 130 ). The spring ( 130 ) biases the locking element ( 100 ) and the actuation button ( 70 ) into their first dose setting position and biases the first ratchet features ( 43 ) into engagement with the second ratchet features ( 121 ).

The present invention is generally directed to an injection device, i.e.a drug delivery device for selecting and dispensing a number of uservariable doses of a medicament.

Pen type drug delivery devices have application where regular injectionby persons without formal medical training occurs. This may beincreasingly common among patients having diabetes where self-treatmentenables such patients to conduct effective management of their disease.In practice, such a drug delivery device allows a user to individuallyselect and dispense a number of user variable doses of a medicament. Thepresent invention is not directed to so called fixed dose devices whichonly allow dispensing of a predefined dose without the possibility toincrease or decrease the set dose.

There are basically two types of drug delivery devices: resettabledevices (i.e., reusable) and non-resettable (i.e., disposable). Forexample, disposable pen delivery devices are supplied as self-containeddevices. Such self-contained devices do not have removable pre-filledcartridges. Rather, the pre-filled cartridges may not be removed andreplaced from these devices without destroying the device itself.Consequently, such disposable devices need not have a resettable dosesetting mechanism. The present invention is applicable for both types ofdevices, i.e. for disposable devices as well as for reusable devices.

A further differentiation of drug delivery device types refers to thedrive mechanism: There are devices which are manually driven, e.g. by auser applying a force to an injection button, devices which are drivenby a spring or the like and devices which combine these two concepts,i.e. spring assisted devices which still require a user to exert aninjection force. The spring-type devices involve springs which arepreloaded and springs which are loaded by the user during doseselecting. Some stored-energy devices use a combination of springpreload and additional energy provided by the user, for example duringdose setting.

These types of pen delivery devices (so named because they oftenresemble an enlarged fountain pen) generally comprise three primaryelements: a cartridge section that includes a cartridge often containedwithin a housing or holder; a needle assembly connected to one end ofthe cartridge section; and a dosing section connected to the other endof the cartridge section.

A cartridge (often referred to as an ampoule) typically includes areservoir that is filled with a medication (e.g., insulin), a movablerubber type bung or stopper located at one end of the cartridgereservoir, and a top having a pierceable rubber seal located at theother, often necked-down, end. A crimped annular metal band is typicallyused to hold the rubber seal in place. While the cartridge housing maybe typically made of plastic, cartridge reservoirs have historicallybeen made of glass.

The needle assembly is typically a replaceable double-ended needleassembly. Before an injection, a replaceable double-ended needleassembly is attached to one end of the cartridge assembly, a dose isset, and then the set dose is administered. Such removable needleassemblies may be threaded onto, or pushed (i.e., snapped) onto thepierceable seal end of the cartridge assembly.

The dosing section or dose setting mechanism is typically the portion ofthe pen device that is used to set (select) a dose. During an injection,a spindle or piston rod contained within the dose setting mechanismpresses against the bung or stopper of the cartridge. This force causesthe medication contained within the cartridge to be injected through anattached needle assembly. After an injection, as generally recommendedby most drug delivery device and/or needle assembly manufacturers andsuppliers, the needle assembly is removed and discarded.

Unpublished application EP 13 163 089.9 describes an injection devicefor setting and dispensing a number of user variable doses of amedicament. The device comprises a housing, a drive member, a lockingelement, a first clutch and an actuation button. The housing defines alongitudinal axis. The drive member is rotationally constrained to thehousing in a first dose setting mode and is rotatable relative to thehousing in a second dose dispensing mode. The locking element ispermanently rotationally constrained to the housing but axially movablerelative to the housing in a direction parallel to the longitudinal axisbetween a first dose setting position and a second dose dispensingposition. The first clutch rotationally couples the drive member to thelocking element when the locking element is in its first dose settingposition and de-couples the drive member and the locking element whenthe locking element is in its second dose dispensing position. Theactuation button is suitable for switching the injection device betweenthe first dose setting mode and the second dose dispensing mode. Theactuation button and the locking element are separate components whichare not attached to each other. However, the actuation button axiallyabuts the locking element such that an axial force may be transmittedfrom the actuation button to the locking element in one direction. Afirst compression spring acts on the actuation button biasing theactuation button in its dose setting mode position. This firstcompression spring further acts on a ratchet between the driver and adose indicator or dose setting member. A second compression spring actson the locking element biasing the locking element in its dose settingposition.

It is an object of the present invention to improve this known devicewith respect to manufacturing costs, complexity of assembly andreliability.

This object is solved by a device as defined in claim 1, with the springbiasing the locking element and the actuation button into their firstdose setting position and in addition biasing the first ratchet featuresinto engagement with the second ratchet features. Thus, one singlespring, preferably a compression spring, is sufficient for biasing theactuation button and the locking element into the dose setting positionor mode. As an ancillary effect, the same spring may be used to keep tworatchet elements into engaging contact, which facilitates dose settingand dose dispensing. In other words, one component required in thedevice of unpublished application EP 13 163 089.9, namely an additionalcompression spring, can be omitted which does not only reduce the costsfor the components of the device but also reduces the time and effortrequired during assembly of the device. With respect to the feature ofthe spring biasing the locking element, this is understood to encompassthe preferred embodiment wherein the locking element is axiallyconstrained to the button and the spring biases the button, effectivelybiasing the locking element.

Preferably, the actuation button is axially constrained and rotatablerelative to the locking element. For example, the actuation button maybe snapped or clipped onto the locking element. This axial constraintresults in the actuation button and the locking element behaving as onesingle component regarding their axial movements. Advantages of thisdesign include that there is no need for a spring to push the lockingarm in the proximal direction during dialing and ease of assemblybecause the button and the locking arm can be assembled together. Theactuation button is preferably provided with a central stem extendingfrom a proximal actuation area. A bead or flange may be provided on thisstem with the compression spring abutting this bead or flange. As analternative, the compression spring may be arranged such that it acts onthe locking element which in turn entrains the actuation button.

Preferably, the locking element comprises an arm portion extendingparallel to the longitudinal axis between the housing and the drivemember. A first clutch may be provided at one end of the arm portion andthe actuation button may be attached to the opposite end of the armportion.

The ratchet permits the dose setting member to rotate during dosesetting without affecting the driver, but ensures that the driver ismoved together with the dose setting member during dose dispensing. Inaddition to dose setting and dose dispensing it may be required tocorrect a dose, i.e. to decrease the set dose. Preferably, the firstratchet features and the second ratchet features comprise teeth havingramp angles allowing overhaul of the ratchet for dose correction. Duringdose setting and during dose correction, the teeth of the ratchetfeatures bump over each other against the force of the spring biasingthese teeth into engagement. Thus, the ratchet allows relativerotational movement between the dose setting member and the drive memberin two opposite directions during dose setting and dose correction.

For an injection device using a torsion spring or the like forgenerating the force or torque required for dose dispensing, the ratchettypically has to withstand this torque or force, which is a function ofthe axial load applied by the spring, the ramp angle of the ratchet, thefriction coefficient between the mating surfaces and the mean radius ofthe ratchet features and the torque applied by the torsion spring. Itmay be desirable to choose different ramp angles for clockwise andanti-clockwise relative rotation of the ratchet features so that thespring torque cannot overhaul the ratchet whilst ensuring the dial-uptorque is as low as possible.

According to a preferred embodiment of the present invention the housinghas a first aperture or window, a dose indicator positioned within thehousing and rotatable with respect to the housing during dose settingand during dose dispensing, and a gauge element, which is interposedbetween the housing and the dose indicator. The gauge element has asecond aperture or window, which is positioned with respect to the firstaperture or window of the housing such that at least a part of the doseindicator is visible through the first and second apertures or windows.Further, the gauge element is axially guided within the housing and inthreaded engagement with the dose indicator such that rotation of thedose indicator causes an axial displacement of the gauge element.

The position of the gauge element may thus be used to identify theactually set and/or dispensed dose. Different colours of sections of thegauge member may facilitate identifying the set and/or dispensed dosewithout reading numbers, symbols or the like on a display. As the gaugeelement is in threaded engagement with the dose indicator, rotation ofthe dose indicator causes an axial displacement of the gauge elementrelative to the dose indicator and relative to the housing. The gaugeelement may have the form of a shield or strip extending in thelongitudinal direction of the device. As an alternative, the gaugeelement may be a sleeve. In an embodiment of the invention, the doseindicator is marked with a sequence of numbers or symbols and the gaugeelement comprises an aperture or window. With the dose indicator locatedradially inwards of the gauge element, this allows that at least one ofthe numbers or symbols on the dose indicator is visible through theaperture or window. In other words, the gauge element may be used toshield or cover a portion of the dose indicator and to allow view onlyon a limited portion of the dose indicator. This function may be inaddition to the gauge element itself being suitable for identifying orindicating the actually set and/or dispensed dose.

The injection device further comprises a resilient member adapted toprovide a force necessary for ejecting a dose from the injection device.Providing a resilient member, such as a spring, generating the force ortorque required for dose dispensing reduces the user applied forces fordose dispensing. This is especially helpful for users with impaireddexterity. In addition, the dial extension of the known manually drivendevices, which is a result of the required dispensing stroke, may beomitted by providing the resilient member because merely a smalltriggering stroke may be necessary for releasing the resilient member.

In general, the concept of the gauge element and the dose indicator isapplicable for various types of devices with or without a drive spring.In the preferred embodiment of the present invention, the resilientmember may be a spring which is preloaded or a spring which is loaded bythe user during dose selecting. This includes devices which use acombination of spring preload and additional energy provided by theuser, for example during dose setting. Preferably, the resilient membermay be a torsion spring which is preferably strained during dosesetting. The torsion spring may have one end attached to the housing andthe other end attached to the dose indicator. As an alternative, theresilient member may comprise a reverse wound flat spiral spring as apower reservoir having a first end attached to a first spool and asecond end attached to a second spool, which is axially and rotationallyconstrained to a drive member, which is for example rotationallyconstrained to a piston rod.

The attachment of e.g. a torsion spring to e.g. the dose indicator hasto be durable and reliable to prevent uncoupling of the spring. Takinginto account efficiency during assembly of an injection device, it isrequired to constrain the spring with a minimum effort. One way toachieve this, may be providing an anchor point or a pocket in the doseindicator or the like component and providing a hook at the end of thespring which is to be attached to the e.g. dose indicator. If a preloadis exerted on the spring, the hook may be biased into engagement withthe anchor point, helping to prevent disassembly during subsequentassembly steps. In addition or as an alternative, a groove may beprovided in the e.g. dose indicator for receiving at least a part of thefirst spring coil, wherein the groove has an end feature that is ininterference with the end of the spring. For example, a ramp may beprovided at the end of a groove which ramp deflects a spring hook or thelike spring end in a radial direction, e.g. radially inwards, generatinga force in the spring, causing a contact force between the ramp and thespring end, and anchoring the spring due to frictional forces. A flangemay be provided for reinforcement of this connection area of the doseindicator or the like.

Preferably, the injection device comprises a lead screw or piston rod,which is driven by the drive member during dose dispensing to act on acartridge bung. If the lead screw rotates during dose dispensing,friction occurs with respect to the (rotationally static) cartridgebung. A bearing may be provided to minimize friction. In a preferredembodiment, the lead screw is provided at its distal end with aninterface for clip attachment of the bearing, wherein the bearing has aconvex contact surface and the lead screw has a concave contact surface.The curvature of the convex contact surface and the concave contactsurface may be chosen such that the contact diameter between the bearingand lead screw is small, to minimize the frictional losses at thisinterface. Attachment of the bearing to the lead screw may be achievedby providing the lead screw with at least one clip arm extending in thedistal direction and defining an insertion space between for insertionof a bearing interface, which may comprise a stem extending in theproximal direction having a recessed portion.

In a preferred embodiment, the dose indicator, during dose setting, isadapted to undergo a mere rotational movement within the housing andrelative to the housing. In other words, the dose indicator does notperform a translational movement during dose setting. This prevents thatthe dose indicator is wound out of the housing or that the housing hasto be prolonged for covering the dose indicator within the housing.

It is preferred if the device is suitable for dispensing variable,user-selectable, doses of medicament. The device may be a disposabledevice, i.e. a device which does not provide for an exchange of an emptycartridge.

According to a preferred embodiment, the drug delivery device comprisesa limiter mechanism defining a maximum settable dose and a minimumsettable dose. Typically, the minimum settable dose is zero (0 IU ofinsulin formulation), such that the limiter stops the device at the endof dose dispensing. The maximum settable dose, for example 60, 80 or 120IU of insulin formulation, may be limited to reduce the risk ofoverdosage and to avoid the additional spring torque needed fordispensing very high doses, while still being suitable for a wide rangeof patients needing different dose sizes. Preferably, the limits for theminimum dose and the maximum dose are provided by hard stop features.The limiter mechanism may comprise a first rotational stop on the doseindicator and a first counter stop on the gauge element, which abut inthe minimum dose (zero) position, and a second rotational stop on thedose indicator and a second counter stop on the gauge element, whichabut in the maximum dose position. As the dose indicator rotatesrelative to the gauge element during dose setting and during dosedispensing, these two components are suitable to form a reliable androbust limiter mechanism.

The drug delivery device may comprise a last dose protection mechanismfor preventing the setting of a dose, which exceeds the amount of liquidleft in a cartridge. This has the advantage that the user knows how muchwill be delivered before starting the dose delivery. It also ensuresthat dose delivery stops in a controlled manner without the bungentering the neck portion of the cartridge where the diameter is smallerwhich may result in an underdose. In a preferred embodiment, this lastdose protection mechanism only detects the medicament remaining in thecartridge when the cartridge contains less than the maximum dose (e.g.120 IU). For example, the last dose protection mechanism comprises a nutmember interposed between the drive member and a component which rotatesduring dose setting and dose dispensing. The component which rotatesduring dose setting and dose dispensing may be the dose indicator or adial sleeve rotationally constrained to the dose indicator. In apreferred embodiment, the dose indicator and/or a dial sleeve rotateduring dose setting and during dose dispensing, whereas the drive memberonly rotates during dose dispensing together with the dose indicatorand/or the dial sleeve. Thus, in this embodiment, the nut member willonly move axially during dose setting and will remain stationary withrespect to these components during dose dispensing. Preferably, the nutmember is threaded to the drive member and splined to the dose indicatorand/or the dial sleeve. As an alternative, the nut member may bethreaded to the dose indicator and/or the dial sleeve and may be splinedto the drive member. The nut member may be a full nut or a part thereof,e.g. a half nut.

The injection device may comprise at least one clicker mechanism forgenerating a tactile and/or audible feedback. During dose settingre-engagement of the ratchet teeth (between the driver and a clutchplate, dose indicator or dose setting member) may generate an audibleand/or tactile feedback. For example, a tactile feedback during dosedispense may be provided via a compliant cantilever clicker armintegrated into the proximal end of the locking element. This clickerarm may interface radially with ratchet features (e.g. a ring of teeth)provided on the outer surface of the proximal end of the dose indicator,whereby the ratchet tooth spacing corresponds to the dose indicatorrotation required for a single increment dispense. During dispense, asthe dose indicator rotates and the locking element is rotationallycoupled to the housing, the ratchet features engage with the clicker armto produce an audible click with each dose increment delivered.

In addition or as an alternative to this feedback during dose dispense,the clicker mechanism signifies the end of dose dispensing. At the endof dose, an audible feedback may be provided in the form of a “click”,distinct from the “clicks” provided during dispense, to inform the userthat the device has returned to its zero position. In a preferredembodiment this feedback is generated by the interaction of threecomponents, the dose indicator, gauge element and locking element with apivotable clicker arm arranged via a torsion beam on the locking elementand with a ratchet feature (e.g. a tooth) provided on the outer surfaceof the dose indicator. The movement of the locking element between itsfirst dose setting position and its second dose dispensing position,together with the movement of the gauge element back towards its zerodose position, may be used to pivot the clicker arm from a non-deflectedposition during dose setting into a position engaging the ratchetfeatures on the dose indicator during dose dispensing. This embodimentallows feedback to only be created at the end of dose delivery and notcreated if the device is dialed back to, or away from, the zeroposition.

In a preferred embodiment of the invention, the device comprises atleast a first clicker producing an audible and/or tactile first feedbackduring dose setting and/or dose dispensing and a second clickerproducing an audible and/or tactile second feedback, distinct from thefirst feedback, during dose dispensing when the device reaches itsminimum dose (zero) position. The injection device may have differentclickers active during dose setting and during dose dispensing.

Spring loaded injection devices often comprise an actuation element forreleasing the energy stored in the resilient member, e.g. in the spring.Typically, the user presses or activates this actuating element after adose has been set to initiate dose dispensing. According to a preferredembodiment, the actuating element is the actuation button for switchingthe injection device between the first dose setting mode and the seconddose dispensing mode. The actuation button may be located at theproximal end of the housing, i.e. the end facing away from the needle.

The injection device may further comprise a second clutch rotationallycoupling the actuation button to the dose indicator when the actuationbutton and the locking element are in the first dose setting positionand de-coupling the actuation button from the dose indicator when theactuation button and the locking element are in the second dosedispensing position. Thus, the actuation button entrains the doseindicator during dose setting, but allows the actuation button to standstill as the dose indicator rotates during dose dispensing.

The drug delivery device may comprise a cartridge containing amedicament. The term “medicament”, as used herein, means apharmaceutical formulation containing at least one pharmaceuticallyactive compound,

wherein in one embodiment the pharmaceutically active compound has amolecular weight up to 1500 Da and/or is a peptide, a proteine, apolysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or afragment thereof, a hormone or an oligonucleotide, or a mixture of theabove-mentioned pharmaceutically active compound,wherein in a further embodiment the pharmaceutically active compound isuseful for the treatment and/or prophylaxis of diabetes mellitus orcomplications associated with diabetes mellitus such as diabeticretinopathy, thromboembolism disorders such as deep vein or pulmonarythromboembolism, acute coronary syndrome (ACS), angina, myocardialinfarction, cancer, macular degeneration, inflammation, hay fever,atherosclerosis and/or rheumatoid arthritis,wherein in a further embodiment the pharmaceutically active compoundcomprises at least one peptide for the treatment and/or prophylaxis ofdiabetes mellitus or complications associated with diabetes mellitussuch as diabetic retinopathy,wherein in a further embodiment the pharmaceutically active compoundcomprises at least one human insulin or a human insulin analogue orderivative, glucagon-like peptide (GLP-1) or an analogue or derivativethereof, or exendin-3 or exendin-4 or an analogue or derivative ofexendin-3 or exendin-4.

Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) humaninsulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) humaninsulin; Asp(B28) human insulin; human insulin, wherein proline inposition B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein inposition B29 Lys may be replaced by Pro; Ala(B26) human insulin;Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) humaninsulin.

Insulin derivates are for example B29-N-myristoyl-des(B30) humaninsulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl humaninsulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin;B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(ω-carboxyheptadecanoyl) human insulin.

Exendin-4 for example means Exendin-4(1-39), a peptide of the sequenceH-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

Exendin-4 derivatives are for example selected from the following listof compounds:

H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2, H-(Lys)5-des Pro36,des Pro37 Exendin-4(1-39)-NH2, des Pro36 Exendin-4(1-39), des Pro36[Asp28] Exendin-4(1-39), des Pro36 [IsoAsp28] Exendin-4(1-39), des Pro36[Met(O)14, Asp28] Exendin-4(1-39), des Pro36 [Met(O)14, IsoAsp28]Exendin-4(1-39), des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39), des Pro36[Trp(O2)25, IsoAsp28] Exendin-4(1-39), des Pro36 [Met(O)14 Trp(O2)25,Asp28] Exendin-4(1-39), des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28]Exendin-4(1-39); or des Pro36 [Asp28] Exendin-4(1-39), des Pro36[IsoAsp28] Exendin-4(1-39), des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39), des Pro36 [Trp(O2)25,Asp28] Exendin-4(1-39), des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39), des Pro36[Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),

wherein the group -Lys6-NH2 may be bound to the C-terminus of theExendin-4 derivative;or an Exendin-4 derivative of the sequence

des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010), H-(Lys)6-des Pro36 [Asp28]Exendin-4(1-39)-Lys6-NH2, des Asp28 Pro36, Pro37,Pro38Exendin-4(1-39)-NH2, H-(Lys)6-des Pro36, Pro38 [Asp28]Exendin-4(1-39)-NH2, H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28]Exendin-4(1-39)-NH2, des Pro36, Pro37, Pro38 [Asp28]Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28]Exendin-4(1-39)-(Lys)6-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28]Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36 [Trp(O2)25, Asp28]Exendin-4(1-39)-Lys6-NH2, H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25]Exendin-4(1-39)-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]Exendin-4(1-39)-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25,Asp28] Exendin-4(1-39)-NH2, des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25,Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38[Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36[Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2, des Met(O)14 Asp28 Pro36,Pro37, Pro38 Exendin-4(1-39)-NH2, H-(Lys)6-desPro36, Pro37, Pro38[Met(O)14, Asp28] Exendin-4(1-39)-NH2, H-Asn-(Glu)5-des Pro36, Pro37,Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, des Pro36, Pro37, Pro38[Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36, Pro37,Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-Asn-(Glu)5 desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25]Exendin-4(1-39)-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]Exendin-4(1-39)-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14,Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, des Pro36, Pro37, Pro38[Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]Exendin-4(S1-39)-(Lys)6-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38[Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;

or a pharmaceutically acceptable salt or solvate of any one of theafore-mentioned Exendin-4 derivative.

Hormones are for example hypophysis hormones or hypothalamus hormones orregulatory active peptides and their antagonists as listed in RoteListe, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin,Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin),Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,Buserelin, Nafarelin, Goserelin.

A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid,a heparin, a low molecular weight heparin or an ultra low molecularweight heparin or a derivative thereof, or a sulphated, e.g. apoly-sulphated form of the above-mentioned polysaccharides, and/or apharmaceutically acceptable salt thereof. An example of apharmaceutically acceptable salt of a poly-sulphated low molecularweight heparin is enoxaparin sodium.

Antibodies are globular plasma proteins (˜150 kDa) that are also knownas immunoglobulins which share a basic structure. As they have sugarchains added to amino acid residues, they are glycoproteins. The basicfunctional unit of each antibody is an immunoglobulin (Ig) monomer(containing only one Ig unit); secreted antibodies can also be dimericwith two Ig units as with IgA, tetrameric with four Ig units liketeleost fish IgM, or pentameric with five Ig units, like mammalian IgM.

The Ig monomer is a “Y”-shaped molecule that consists of fourpolypeptide chains; two identical heavy chains and two identical lightchains connected by disulfide bonds between cysteine residues. Eachheavy chain is about 440 amino acids long; each light chain is about 220amino acids long. Heavy and light chains each contain intrachaindisulfide bonds which stabilize their folding. Each chain is composed ofstructural domains called Ig domains. These domains contain about 70-110amino acids and are classified into different categories (for example,variable or V, and constant or C) according to their size and function.They have a characteristic immunoglobulin fold in which two β sheetscreate a “sandwich” shape, held together by interactions betweenconserved cysteines and other charged amino acids.

There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ,and μ. The type of heavy chain present defines the isotype of antibody;these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies,respectively.

Distinct heavy chains differ in size and composition; α and γ containapproximately 450 amino acids and δ approximately 500 amino acids, whileμ and ε have approximately 550 amino acids. Each heavy chain has tworegions, the constant region (CH) and the variable region (VH). In onespecies, the constant region is essentially identical in all antibodiesof the same isotype, but differs in antibodies of different isotypes.Heavy chains γ, α and δ have a constant region composed of three tandemIg domains, and a hinge region for added flexibility; heavy chains μ andε have a constant region composed of four immunoglobulin domains. Thevariable region of the heavy chain differs in antibodies produced bydifferent B cells, but is the same for all antibodies produced by asingle B cell or B cell clone. The variable region of each heavy chainis approximately 110 amino acids long and is composed of a single Igdomain.

In mammals, there are two types of immunoglobulin light chain denoted byλ and κ. A light chain has two successive domains: one constant domain(CL) and one variable domain (VL). The approximate length of a lightchain is 211 to 217 amino acids. Each antibody contains two light chainsthat are always identical; only one type of light chain, κ or λ, ispresent per antibody in mammals.

Although the general structure of all antibodies is very similar, theunique property of a given antibody is determined by the variable (V)regions, as detailed above. More specifically, variable loops, threeeach the light (VL) and three on the heavy (VH) chain, are responsiblefor binding to the antigen, i.e. for its antigen specificity. Theseloops are referred to as the Complementarity Determining Regions (CDRs).Because CDRs from both VH and VL domains contribute to theantigen-binding site, it is the combination of the heavy and the lightchains, and not either alone, that determines the final antigenspecificity.

An “antibody fragment” contains at least one antigen binding fragment asdefined above, and exhibits essentially the same function andspecificity as the complete antibody of which the fragment is derivedfrom. Limited proteolytic digestion with papain cleaves the Ig prototypeinto three fragments. Two identical amino terminal fragments, eachcontaining one entire L chain and about half an H chain, are the antigenbinding fragments (Fab). The third fragment, similar in size butcontaining the carboxyl terminal half of both heavy chains with theirinterchain disulfide bond, is the crystalizable fragment (Fc). The Fccontains carbohydrates, complement-binding, and FcR-binding sites.Limited pepsin digestion yields a single F(ab′)2 fragment containingboth Fab pieces and the hinge region, including the H-H interchaindisulfide bond. F(ab′)2 is divalent for antigen binding. The disulfidebond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, thevariable regions of the heavy and light chains can be fused together toform a single chain variable fragment (scFv).

Pharmaceutically acceptable salts are for example acid addition saltsand basic salts. Acid addition salts are e.g. HCl or HBr salts. Basicsalts are e.g. salts having a cation selected from alkali or alkaline,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), whereinR1 to R4 independently of each other mean: hydrogen, an optionallysubstituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenylgroup, an optionally substituted C6-C10-aryl group, or an optionallysubstituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are described in “Remington'sPharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), MarkPublishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia ofPharmaceutical Technology.

Pharmaceutically acceptable solvates are for example hydrates.

Non-limiting, exemplary embodiments of the invention will now bedescribed with reference to the accompanying drawings, in which:

FIG. 1 shows an exploded view of the components of an injection devicein accordance with a first embodiment of the present invention;

FIG. 2 shows a top view of the device of FIG. 1 in the minimum doseposition;

FIG. 3 shows a top view of the device of FIG. 1 with a dose of 111 unitsset;

FIG. 4 shows a sectional view of the device of FIG. 1;

FIG. 5 shows an enlarged view of a detail of the device of FIG. 1 in thedose setting mode;

FIG. 6 shows the enlarged view of a detail of FIG. 5 in the dosedispensing mode;

FIG. 7 shows a perspective view of the gauge element of the device ofFIG. 1;

FIG. 8 shows a perspective view of the dose indicator of the device ofFIG. 1;

FIG. 9 shows an enlarged detail of the dose indicator of FIG. 8;

FIG. 9a shows an enlarged detail of FIG. 9;

FIG. 9b shows an alternative enlarged detail of FIG. 9;

FIG. 10 shows a perspective view of the torsion spring of the device ofFIG. 1;

FIG. 11 shows an enlarged detail of the driver of the device of FIG. 1;

FIG. 12 shows an enlarged detail of the driver, the clutch plate and theclutch spring of the device of FIG. 1;

FIG. 13 shows an enlarged detail of the driver and the nut of the deviceof FIG. 1;

FIG. 14 shows an enlarged detail of the button of the device of FIG. 1;

FIG. 15 shows an enlarged detail of the dose indicator of the device ofFIG. 1;

FIG. 16 shows an enlarged detail of the lead screw and bearing of thedevice of FIG. 1;

FIG. 17 shows an enlarged detail of the lead screw of the device of FIG.1;

FIG. 18 shows an enlarged detail of the locking element of the device ofFIG. 1;

FIG. 19 shows an enlarged detail of the locking element and button ofthe device of FIG. 1;

FIG. 20 shows a partially cut away view of the device of FIG. 1; and

FIGS. 21 a-f show in enlarged views the sequence of generating a clickat the end of dose dispensing.

FIG. 2 shows a drug delivery device in the form of an injection pen. Thedevice has a distal end (left end in FIG. 2) and a proximal end (rightend in FIG. 2). The component parts of the drug delivery device areshown in FIG. 1. The drug delivery device comprises a housing 10, acartridge holder 20, a lead screw (piston rod) 30, a driver 40, a nut50, a dose indicator (number sleeve) 60, a button 70, a dose selector80, a torsion spring 90, a locking arm 100, a gauge element 110, aclutch plate 120, a clutch spring 130, a bearing 140 and a cartridge150. A needle arrangement (not shown) with a needle hub and a needlecover may be provided as additional components, which can be exchangedas explained above. A longitudinal axis I of the device is shown in FIG.4.

The housing 10 or body is a generally tubular element. In the embodimentshown in the figures, the housing 10 provides location for the liquidmedication cartridge 150 and cartridge holder 20, an interface toprevent rotation of the locking arm 100 and the gauge element 110, aslot 11 or lens through which the dose number on the dose indicator 60can be viewed, and a feature, e.g. a circumferential groove, on itsexternal surface to axially retain the dose selector 80. A flange-likeor cylindrical inner wall 12 comprises an inner thread engaging thepiston rod 30.

The cartridge holder 20 is located at the distal side of housing 10 andpermanently attached thereto. The cartridge holder may be a transparentor translucent component which is tubular to receive cartridge 150. Thedistal end of cartridge holder 20 may be provided with means forattaching a needle arrangement. A removable cap (not shown) may beprovided to fit over the cartridge holder 20 and may be retained viaclip features.

The lead screw 30 is an elongate member with an outer thread 31 (FIG.16) which is rotationally constrained to the driver 40 via a splinedinterface. The thread 31 may have a large lead-in, for example a wedgeshape form, at its distal end to engage a corresponding housing threadform on the first rotation. The interface comprises at least onelongitudinal groove or track 32 (FIG. 17) and a corresponding protrusionor spline of the driver 40. When rotated, the lead screw 30 is forced tomove axially relative to the driver 40, through its threaded interfacewith the housing 10. At its distal end, the lead screw 30 is providedwith an interface for clip attachment of the bearing 140. In the presentembodiment, this interface comprises two clip arms 33 extending in thedistal direction defining an insertion space between them for insertionof a bearing 140 interface. As an alternative, the interface maycomprise only one single clip arm extending more than 180° about thelongitudinal axis, or may comprise one or several clip arms 33. The cliparm(s) 33 may have a bended form with a recessed clip portion as shownin FIG. 17. Preferably, the clip arm(s) form a cylindrical outer facehaving a diameter equal to or smaller than the outer diameter of thelead screw 30 at the ground of the groove (flute base) of the outerthread 31. A concave contact surface 34 is provided between the cliparms 33 for abutment of a corresponding portion of bearing 140.

The driver 40 is a sleeve which extends from the interface with the doseindicator (number sleeve) 60 via the clutch plate 120 down to a splinedtooth interface 41 (FIG. 11) with the locking arm 100. This providesrotational constraint of the locking arm 100 to the driver 40 duringdose setting. When the button 70 is pressed, these spline teeth aredisengaged allowing the driver 40 to rotate. Further, teeth 42 areprovided near the proximal end on a flange 43 of driver 40 forengagement with clutch plate 120 (FIG. 12). The driver 40 has a threadedsection 44 providing a helical track for the nut 50 (FIG. 13). Inaddition, a last dose abutment or stop 46 is provided which may be theend of the thread 44 track or preferably a rotational hard stop forinteraction with a corresponding last dose stop 51 of nut 50, thuslimiting movement of the nut 50 on the thread 44. At least onelongitudinal spline 45 engages a corresponding track 32 of the leadscrew 30.

The nut 50 is part of a last dose limiter mechanism. The nut 50 islocated between the dose indicator (number sleeve) 60 and the driver 40.It is rotationally constrained to the dose indicator 60 via a splinedinterface. It moves along a helical path relative to the driver 40, viaa threaded interface 44, when relative rotation occurs between the doseindicator 60 and driver 40 during dialing. This is shown in FIG. 13. Asan alternative, the nut 50 may be splined to the driver 40 and threadedto the dose indicator 60. In the embodiment shown in the Figures, thenut 50 is a full nut, but in alternative embodiments it may be a halfnut, i.e. a component extending approximately 180° around the centeraxis of the device. As a further alternative, if the driver 40 wasformed from two separate components that became rigidly engaged duringassembly then the nut 50 could also be a complete nut.

The dose indicator (number sleeve) 60 is a tubular element as shown inFIGS. 8 and 9. In the embodiment depicted in the Figures the doseindicator is a sub assembly comprising a number sleeve lower 61 and anumber sleeve upper 62 which are rigidly fixed to each other duringassembly to form the dose indicator. The number sleeve lower and thenumber sleeve upper are separate components only to simplify mouldtooling and assembly. However, they could be integrated into a singlecomponent part. This sub assembly is constrained to the housing 10 byfeatures towards the proximal end to allow rotation but not translation.The number sleeve lower is marked with a sequence of numbers, which arevisible through the gauge element 110 and the window (slot 11) throughthe housing 10, to denote the dialed dose of medicament. Further, thenumber sleeve lower 61 has a portion with an outer thread 63 engagingthe gauge element 110. End stops 64, 65 are provided at the oppositeends of thread 63 to limit relative movement with respect to the gaugeelement 110. Clicker features 66 a are provided on number sleeve upper62 for engaging a corresponding clicker feature of the locking element100 during dose dispensing (FIG. 15 and FIG. 18). Clutch features 66 bare provided inwardly directed on number sleeve upper 62 for engagementwith splines 73 of the button 70 during dose setting and dose correction(FIG. 14 and FIG. 15). A further clicker feature 66 c interacts withclicker arm 105. In addition, the number sleeve lower 61 is rotationallyconstrained to the nut 50 and to the clutch plate 120 via a splinedinterface comprising at least one longitudinal spline 67 (FIG. 9). Aninterface for attachment of the torsion spring 90 to the number sleevelower 61 comprises large lead-ins and a groove feature 68 with a pocket(anchor point 69 a, 69 c) for receiving a first coil or hook portion 91of the spring (FIG. 10). The groove 68 has an end feature in the form ofa ramp 69 b, 69 d that is in interference with the hook portion 91 ofthe spring. An inner flange is shown in FIG. 9 for reinforcing the areaof the dose indicator connected to the torsion spring 90. The design ofthe groove 68 is such that the spring 90 may be received within thepocket without interfering with the gauge element 110. Two embodimentsof an anchor point 69 a and 69 c and an end feature 69 b and 69 d in theform of a ramp are shown in FIGS. 9a and 9 b.

The button 70 forms the proximal end of the device. The button ispermanently splined to the dose selector 80 and splined to the numbersleeve upper 62 when the button is not pressed. This spline interface isdisconnected when the button 70 is pressed. A central stem 71 extendsdistally from the proximal actuation face of the button 70. The stem 71is provided with a flange 72 carrying splines 73 for engagement withsplines 66 b of the number sleeve upper 62 (FIG. 14 and FIG. 15). Thebutton 70 has a discontinuous annular skirt forming two clips 74 foraxially constraining the button to a bead or flange of the lockingelement 100. Further spline features for engagement with the doseselector 80 are provided by the radially extending surfaces on the sidesof the clips 74. A slit 75 is provided for making the clips moreflexible.

The dose selector 80 or dose dial grip is a sleeve-like component with aserrated outer skirt. The dose selector 80 is axially constrained to thehousing 10. It is rotationally constrained, via a splined interface, tothe dose button 70. This splined interface which includes grooves 81interacting with the spline features 75 remains engaged irrespective ofthe dose button 70 axial positions.

The torsion spring 90 is attached with its distal end to the housing 10and with its other end to the number sleeve lower 61. The torsion spring90 is pre-wound upon assembly, such that it applies a torque to the doseindicator 60 when the mechanism is at zero units dialed. The action ofrotating the dose selector 80, to set a dose, rotates the dose indicator60 relative to the housing 10, and charges the torsion spring 90further. The torsion spring 90 is located inside the dose indicator 60and surrounds a distal portion of the driver 40. As shown in FIG. 10,the spring has a hook 91 at one end for attachment on the dose indicator60. A similar hook end may be provided at the opposite end forattachment on the housing.

The locking element 100 is rotationally fixed to the housing 10 butallowed to translate axially. Axial movement is effected and controlledby the dose button 70 which is axially clipped onto the locking element100 (FIG. 18). The locking element 100 comprises a proximal ring portion101 and an arm portion 102 extending distally from the ring portion.Near its distal end, the arm portion 102 has teeth 103 for releasablycoupling the tooth interface 41 of driver 40 to the housing 10 via thelocking element 100 (FIG. 11). Further, a compliant cantilever clickerarm 104 is arranged within the ring portion 101 to produce a tactilefeedback due to an engagement with splines 66 a on the number sleeveupper 62 when the locking element is in its dose dispensing position. Anadditional clicker arm 105 is pivotally arranged on a torsion beam andinteracts with clicker features on the dose indicator 60 at the end ofdose dispensing (FIG. 20).

The gauge element 110 is a window element which is constrained toprevent rotation but allow translation relative to the housing 10 via asplined interface. It is also in threaded engagement to the doseindicator 60 such that rotation of the dose indicator 60 causes axialtranslation of the gauge element 110. The gauge element 110 ispositioned in housing 10 such that it is guided within slot 11 andcloses same. As shown in FIG. 7, it is a generally plate or band likecomponent having a central aperture 111 or window and two flanges 112,113 extending on either side of the aperture. The flanges 112, 113 arepreferably not transparent and thus shield or cover the dose indicator60, whereas the aperture 111 or window allows viewing a portion of thenumber sleeve lower 61. Further, gauge element 110 has a ramp 114interacting with a clicker arm 105 of the locking element 100 at the endof dose dispensing (FIG. 20). The gauge element 110 has helical features115 on its inner surface which engage with the helical thread cut in thenumber sleeve lower 61 such that rotation of the dose indicator 60causes axial translation of the gauge element. These helical features115 on the gauge element 110 also create stop abutments against the endof the helical cut in the dose indicator 60 to limit the minimum andmaximum dose that can be set.

The clutch plate 120 is a ring-like component (FIG. 12) arranged on theproximal end of the driver 40 near flange 42. It is surrounded by thedose indicator 60 and splined thereto by spline 67. It is also coupledto the driver 40 via a ratchet interface 43, 121, which occurs on anaxial abutment. The ratchet 43, 121 provides a detented position betweenthe dose indicator 60 and driver 40 corresponding to each dose unit, andengages different ramped tooth angles during clockwise andanti-clockwise relative rotation. FIG. 12 shows the clutch plate 120together with the proximal end of the device in more detail.

The clutch spring 130 is a compression spring located interposed betweenflange 72 of button 70 and clutch plate 120. It acts on the clutch plate120 allowing the ratchet teeth 43, 121 to bump over each other duringdose setting against the axial force of the spring. The axial positionof the locking element 100, clutch plate 120 and button 70 is defined bythe action of the clutch spring 130, which applies a force on the button70 in the proximal direction. This force is reacted by the clutch plate,via the driver 40, to the housing 10 and ensures that the ratchetinterface is always engaged. In the “at rest” position, this ensuresthat the button splines are engaged with the number sleeve upper 62, andthe teeth 41 of driver 40 are engaged with the locking element 100 andthat the ratchet interface is engaged.

The bearing 140 is axially constrained to the lead screw 30 (FIG. 16)and acts on the bung within the liquid medicament cartridge 150. It isaxially clipped to the lead screw 30, but free to rotate. The bearing140 comprises a disc 141 having a stem 142 extending in the proximaldirection. The stem 142 has at its proximal end a convex contact surface143. In addition, a recessed portion 144 is provided on the stem 142.The curvature of the convex contact surface 143 and the concave contactsurface 34 is chosen such that the contact diameter between the bearing140 and lead screw 30 is small to minimize the frictional losses at thisinterface. The design of the clip interface between bearing 140 and leadscrew 30 permits the lead screw 30 to be assembled axially, from theproximal end and through the thread engagement to the housing 10, whichsimplifies assembly. In addition, this design allows a simple “open andshut” mould tooling for both components.

The cartridge 150 is received in cartridge holder 20 (FIG. 4). Thecartridge 150 may be a glass ampoule having a moveable rubber bung 151at its proximal end. The distal end of cartridge 150 is provided with apierceable rubber seal which is held in place by a crimped annular metalband. In the embodiment depicted in the Figures, the cartridge 150 is astandard 1.5 ml cartridge. The device is designed to be disposable inthat the cartridge 150 cannot be replaced by the user or health careprofessional. However, a reusable variant of the device could beprovided by making the cartridge holder 20 removable and allowingbackwinding of the lead screw 30 and the resetting of nut 50.

With the device in the ‘at rest’ condition (e.g. FIGS. 2, 4 and 5), thedose indicator 60 is positioned against its zero dose abutment with thegauge element 110 and the button 70 is not depressed. Dose marking ‘0’on the dose indicator 60 is visible through the window 11 of the housing10 and gauge element 110. The Torsion Spring, which has a number ofpre-wound turns applied to it during assembly of the device, applies atorque to the dose indicator 60 and is prevented from rotating by thezero dose abutment 64 between dose indicator 60 and gauge element 110.

The automated assembly of the torsion spring 90 into the dose indicator60 (FIGS. 9 and 9 a) can be achieved by incorporating large lead-ins andthe groove feature 68 to the dose indicator 60. As the torsion spring 90is rotated during assembly, the hook end form locates in the groovefeature 68 before engaging the anchor point 69 a in the dose indicator60. To help to prevent the torsion spring 90 disengaging the anchorpoint during subsequent assembly steps it is possible to create aninterference. This interference occurs between the outer surface of thehook end and the outer surface of the groove in the dose indicator 60.In an alternative embodiment (FIG. 9b ), it occurs between the innersurface of the hook end and the outer surface of the anchor point 69 cin the dose indicator 60.

The user selects a variable dose of liquid medicament by rotating thedose selector 80 clockwise, which generates an identical rotation in thedose indicator 60. Rotation of the dose indicator 60 causes charging ofthe torsion spring 90, increasing the energy stored within it. As thedose indicator 60 rotates, the gauge element 110 translates axially dueto its threaded engagement with the number sleeve lower 61 therebyshowing the value of the dialed dose (FIG. 7). The gauge element 110 hasflanges 112, 113 either side of the window area 111 which cover thenumbers printed on the dose indicator 60 adjacent to the dialed dose toensure only the set dose number is made visible to the user.

One specific element of this mechanism is inclusion of a visual feedbackfeature in addition to the discrete dose number display typical ondevices of this type. The distal end of the gauge element 110 creates asliding scale (although this could be formed using a separate componentengaged with the dose indicator 60 on a different helical track ifdesired) through the small window 11 in the housing 10. As a dose isset, by the user, the gauge element 110 translates axially, the distancemoved proportional to the magnitude of the dose set. FIGS. 2 and 3 showthe device with a dose of zero set (FIG. 2) and a dose of 111 units set(FIG. 3). A comparison of FIGS. 2 and 3 reveals that window area 111moves from the distal side to the proximal side as an increasing dose isset. This feature gives clear feedback to the user regarding theapproximate size of the dose set. The dispense speed of an auto-injectormechanism may be higher than for a manual injector device, so it may notbe possible to read the numerical dose display during dispense. Thegauge feature provides feedback to the user during dispense regardingdispense progress without the need to read the dose number itself.

The gauge display may be formed by an opaque sliding element revealing acontrasting coloured component underneath. Alternatively, the revealablecomponent may be printed with coarse dose numbers or other indices toprovide more precise resolution. In addition, the gauge displaysimulates a syringe action during dose set and dispense.

The mechanism utilizes a dose selector 80 with an increased diameterrelative to the housing 10 which aids dialing although this is not arequirement of the mechanism. This feature is particularly useful (butnot essential) for an auto-injector mechanism where a power supply ischarged during dose setting and the torque required to turn the doseselector 80 may be higher than for a non-auto injector device.

The driver 40 is prevented from rotating as the dose is set and the doseindicator 60 rotated, due to the engagement of its splined teeth 41 withthe locking element 100 (FIG. 11). Relative rotation must thereforeoccur between the clutch plate 120 and driver 40 via the ratchetinterface (FIG. 12).

The user torque required to rotate the dose selector 80 is a sum of thetorque required to wind up the torsion spring 90, and the torquerequired to overhaul the ratchet feature 43, 121. The clutch spring 130is designed to provide an axial force to the ratchet feature and to biasthe clutch plate 120 onto the driver 40. This axial load acts tomaintain the ratchet teeth engagement of the clutch plate 120 and driver40.

As the user rotates the dose selector 80 sufficiently to increment themechanism by 1 increment, the dose indicator 60 rotates relative to thedriver 40 by 1 ratchet tooth 43, 121. At this point the ratchet teethre-engage into the next detented position. An audible click is generatedby the ratchet re-engagement, and tactile feedback is given by thechange in torque input required.

Relative rotation of the dose indicator 60 and the driver 40 also causesthe last dose nut 50 with stop 51 to travel along its threaded path 44,towards its last dose abutment stop 46 on the driver 40 (FIG. 13).

With no user torque applied to the dose selector 80, the dose indicator60 is now prevented from rotating back under the torque applied by thetorsion spring 90, solely by the ratchet engagement between the clutchplate 120 and the driver 40. The torque necessary to overhaul theratchet 43, 121 in the anti-clockwise direction is a function of theaxial load applied by the clutch spring 130, the anti-clockwise rampangle of the ratchet, the friction coefficient between the matingsurfaces and the mean radius of the ratchet features 43, 121.

The torque necessary to overhaul the ratchet 43, 121 must be greaterthan the torque applied to the dose indicator 60 (and hence clutch plate120) by the torsion spring 90. The ratchet ramp angle is thereforeincreased in the anti-clockwise direction to ensure this is the casewhilst ensuring the dial-up torque is as low as possible.

The user may now choose to increase the selected dose by continuing torotate the dose selector 80 in the clockwise direction. The process ofoverhauling the ratchet interfaces 43, 121 between the dose indicator 60and driver 40 is repeated for each dose increment. Additional energy isstored within the torsion spring 90 for each dose increment and audibleand tactile feedback is provided for each increment dialed by there-engagement of the ratchet teeth 43, 121. The torque required torotate the dose selector 80 increases as the torque required to wind upthe torsion spring 90 increases. The torque required to overhaul theratchet in the anti-clockwise direction must therefore be greater thanthe torque applied to the dose indicator 60 by the torsion spring 90when the maximum dose has been reached.

If the user continues to increase the selected dose until the maximumdose limit is reached, the dose indicator 60 engages with its maximumdose abutment 65 (FIG. 8) on the gauge element 110. This preventsfurther rotation of the dose indicator 60, clutch plate 120 and doseselector 80.

Depending on how many increments have already been delivered by themechanism, during selection of a dose, the last dose stop 51 on the lastdose nut 50 may contact the last dose stop 46 on the driver 40 (FIG.13). The abutment prevents further relative rotation between the doseindicator 60 and the driver 40, and therefore limits the dose that canbe selected. The position of the last dose nut 50 is determined by thetotal number of relative rotations between the dose indicator 60 anddriver 40, which have occurred each time the user sets a dose.

With the mechanism in a state in which a dose has been selected, theuser is able to deselect any number of increments from this dose.Deselecting a dose is achieved by the user rotating the dose selector 80anti-clockwise. The torque applied to the dose selector 80 by the useris sufficient, when combined with the torque applied by the torsionspring 90, to overhaul the ratchet 43, 121 between the clutch plate 120and driver 40 in the anti-clockwise direction (FIG. 12). When theratchet is overhauled, anti-clockwise rotation occurs in the doseindicator 60 (via the clutch plate 120), which returns the doseindicator 60 towards the zero dose position, and unwinds the torsionspring 90. The relative rotation between the dose indicator 60 anddriver 40 causes the last dose nut 50 to return along its helical path,away from the last dose stop 46 (FIG. 13).

With the mechanism in a state in which a dose has been selected, theuser is able to activate the mechanism to commence delivery of a dose.Delivery of a dose is initiated by the user depressing the button 70axially. FIG. 6 shows the device with button 70 pressed.

When the button 70 is depressed, splines 66 b, 73 between the button 70and dose indicator 60 are disengaged (FIG. 14 and FIG. 15), rotationallydisconnecting the button 70 and dose selector 80 from the deliverymechanism (so that the dose selector 80 does not rotate duringdispense). The button 70 acts on the locking element 100, which travelsaxially and disconnects the splined engagement 41, 103 with the driver40 (FIG. 11). The driver 40 can now rotate and is driven by the torsionspring 90 via the dose indicator 60, and clutch plate 120. Rotation ofthe driver 40 causes the lead screw 30 to rotate due to their splinedengagement, and the lead screw 30 then advances due to its threadedengagement to the housing 10. The dose indicator 60 rotation also causesthe gauge element 110 to traverse axially back to its zero positionwhereby the zero dose abutment 64 stops the mechanism (FIG. 10).

The bearing 140 is axially clipped to the lead screw 30, but free torotate. Since the bearing is in direct contact with the bung 151, itdoes not rotate as the lead screw 30 rotates and advances during dosedispense.

Tactile feedback during dose dispense is provided via a compliantcantilever clicker arm 104 integrated into the proximal ring portion 101of the locking element 100 (FIG. 18). This interfaces radially withratchet features on the outer surface of the proximal end of the doseindicator 60 (FIG. 15), whereby the ratchet tooth spacing corresponds tothe dose indicator 60 rotation required for a single increment dispense.During dispense, as the dose indicator 60 rotates and the lockingelement 100 is rotationally coupled to the housing 10, the ratchetfeatures engage with the clicker arm 104 to produce an audible clickwith each dose increment delivered.

Delivery of a dose continues via the mechanical interactions describedabove while the user continues to depress the button 70. If the userreleases the button 70, the clutch spring 130 returns the button 70 toits ‘At Rest’ position, withdrawing the locking element 100 through theaxial constraint between these two components, engaging the splines 41,103 to the driver 40, preventing further rotation and stopping dosedelivery (FIG. 11).

During delivery of a dose, the driver 40 and dose indicator 60 rotatetogether, so that no relative motion in the last dose nut 50 occurs. Thelast dose nut 50 therefore travels axially on the driver 40 duringdialing only.

Once the delivery of a dose is stopped, by the dose indicator 60returning to the zero dose abutment 64, the user may release the button70, which will re-engage the locking element 100 spline teeth 41, 103with the driver 40. The mechanism is now returned to the ‘At Rest’condition.

It is possible to angle the spline teeth 41, 103 on either the driver 40or locking element 100 so that when the button 70 is released there-engagement of the spline teeth fractionally ‘backwinds’ the driver 40thereby removing the engagement of the dose indicator 60 to the gaugeelement 110 zero dose stop abutment. This compensates for the effect ofclearances in the mechanism (for example due to tolerances) which couldotherwise lead to slight advancement of the lead screw 30 and medicamentdispense when the device is dialed for the subsequent dose (due to thedose indicator 60 zero dose stop no longer restraining the mechanism andinstead the restraint returning to the splines between the driver 40 andlocking element 100).

At the end of dose, additional audible feedback is provided in the formof a “click”, distinct from the “clicks” provided during dispense, toinform the user that the device has returned to its zero position viathe interaction of three components, the dose indicator 60, gaugeelement 110 and locking element 100. This embodiment allows feedback toonly be created at the end of dose delivery and not created if thedevice is dialed back to, or away from, the zero position. FIGS. 20 and21 a show the position of the features when the device is in the doseset condition. It can be seen that the gauge element 110 does notcontact the clicker arm 105 of the locking element 100 when the deviceis in the “at rest” condition, i.e. 0 units dialed and the button 70 notpressed. Therefore, during storage the clicker arm 105 is not deflected(and will not suffer creep deformation).

During dose delivery, the locking element 100 is translated axially,whereby the clicker arm 105 on the locking element 100 axially alignswith the clicker feature x66 c on the dose indicator 60. As the gaugeelement 110 returns axially to the zero unit position, the ramp feature114 contacts the clicker arm 105. This causes the clicker arm 105 torock (through twisting of the torsion beam) and, as the end contactingthe gauge element 110 is deflected radially outward, the opposite end isdeflected radially inwards to force the clicker arm tooth intoengagement with the dose indicator 60 clicker feature 66 c.

FIGS. 21a to 21f show the component interactions. In FIG. 21a a dose isdialed with approximately one full dial turn applied to the numbersleeve (dose indicator 60). The gauge element 110 is translated in theproximal direction away from the zero unit position. Clicker arm 105 ofthe locking element 100 is not deflected. In FIG. 21b dose dispensingstarts as the button 70 is depressed which translates locking element100 axially, whereby the clicker arm 105 on the locking element 100axially aligns with the protrusion on the dose indicator 60. At thistime, the clicker arm 105 is still not deflected. FIG. 21c shows the endof dispensing with only 4 units remaining to be dispensed. As the gaugeelement 110 returns axially to the zero unit position, the ramp 114contacts the clicker arm 105. This causes the clicker arm 105 to rock(around the torsion beam) and, as the end contacting the gauge element110 is deflected radially outward, the opposite end is deflectedradially inwards. In FIG. 21d dispensing continues with only 0.5 unitsremaining. As the clicker feature on dose indicator 60 rotates past thetooth on clicker arm 105, the clicker arm is “charged” and deflectedradially outwards. In FIG. 21e the dose is fully dispensed. As clickerramp on dose indicator 60 continues to rotate, the tooth on the clickerarm 105 drops off the sharp edge of the clicker feature on the doseindicator 60 and creates a distinct “click”. In FIG. 21f button 70 isreleased which allows the clutch spring 130 to return the button 70 andthe locking element 100 to their “at rest” axial positions. This alsoallows the clicker arm 105 to rock back to its original position as thetorsion beam relaxes. This arrangement prevents any of these featuresremaining stressed for significant periods of time, minimising the riskof creep deformation.

REFERENCE NUMERALS

-   10 housing-   11 slot-   12 flange-like inner wall-   20 cartridge holder-   30 lead screw (piston rod)-   31 outer thread-   32 longitudinal groove (track)-   33 clip arm-   34 concave contact surface-   40 driver-   41 splined tooth interface-   42 teeth-   43 flange (with teeth)-   44 threaded section-   45 spline-   46 last dose stop-   50 nut-   51 last dose stop-   60 dose indicator (number sleeve)-   61 number sleeve lower-   62 number sleeve upper-   63 outer thread-   64, 65 end stop-   66 a clicker feature (spline)-   66 b clutch feature (spline)-   66 c clicker feature-   67 spline-   68 groove-   69 ramp-   69 a anchor point-   69 b end feature-   69 c anchor point-   69 d end feature-   70 button-   71 stem-   72 flange-   73 spline-   74 clip-   75 slit-   80 dose selector-   81 groove-   90 torsion spring-   91 hook-   100 locking arm-   101 proximal ring portion-   102 arm portion-   103 teeth-   104, 105 clicker arm-   110 gauge element-   111 aperture-   112, 113 flange-   114 ramp-   115 helical feature-   120 clutch plate-   121 ratchet interface-   130 clutch spring-   140 bearing-   141 disc-   142 stem-   143 convex contact surface-   144 recessed portion-   150 cartridge-   151 bung

1. An injection device for setting and dispensing a number of uservariable doses of a medicament comprising a housing (10) having alongitudinal axis (I), a dose setting member (60; 80) rotatable relativeto the housing (10) during dose setting, a drive member (40) which isrotationally constrained to the housing (10) in a first dose settingmode and which is rotatable relative to the housing (10) in a seconddose dispensing mode, a locking element (100) which is permanentlyrotationally constrained to the housing (10) and movable relative to thehousing (10) in a direction parallel to the longitudinal axis (I)between a first dose setting position and a second dose dispensingposition, an actuation button (70) movable relative to the housing (10)in a direction parallel to the longitudinal axis (I) between a firstdose setting position and a second dose dispensing position forswitching the injection device between the first dose setting mode andthe second dose dispensing mode, a ratchet (42, 120) for transmittingtorque from the dose setting member (60) to the drive member (40) duringdose dispensing and allowing relative rotational movement between thedose setting member (60) and the drive member (40) during dose setting,the ratchet (42, 120) comprising first ratchet features (43)rotationally constrained to the driver (40) and second ratchet features(121) rotationally constrained to the dose setting member (60), and aspring (130), wherein the spring (130) biases the locking element (100)and the actuation button (70) into their first dose setting position andbiases the first ratchet features (43) into engagement with the secondratchet features (121).
 2. The injection device according to claim 1,wherein the actuation button (70) is axially constrained and rotatablerelative to the locking element (100).
 3. The injection device accordingto any of the preceding claims, wherein the the first ratchet features(43) and the second ratchet features (121) comprise teeth having rampangles allowing to overhaul the ratchet (42, 120) for dose correction.4. The injection device according to any of the preceding claims,further comprising a first clutch (41, 103) for rotationally couplingthe drive member (40) to the locking element (100) when the lockingelement (100) is in its first dose setting position and de-coupling thedrive member (40) and the locking element (100) when the locking element(100) is in its second dose dispensing position.
 5. The injection deviceaccording to claim 4, wherein the locking element (100) comprises an armportion (102) extending parallel to the longitudinal axis (I) betweenthe housing (10) and the drive member (40) with the first clutch (103)being provided at one end of the arm portion (102) and the actuationbutton (70) being attached to the opposite end of the arm portion (102).6. The injection device according to any of the preceding claims,wherein the housing (10) has a first aperture (11) or window, with thedevice comprising a dose indicator (60) positioned within the housing(10) and rotatable with respect to the housing (10) during dose settingand during dose dispensing, a gauge element (110), which is interposedbetween the housing (10) and the dose indicator (60), wherein the gaugeelement (110) has a second aperture (111) or window, which is positionedwith respect to the first aperture (11) or window of the housing (10)such that at least a part of the dose indicator (60) is visible throughthe first and second apertures (11, 111) or windows, and wherein thegauge element (110) is axially guided within the housing (10) and inthreaded engagement with the dose indicator (60) such that rotation ofthe dose indicator (60) causes an axial displacement of the gaugeelement (110), and a resilient member (90) adapted to provide a forcenecessary for ejecting a dose from the injection device.
 7. Theinjection device according to claim 6, wherein the resilient member (90)is a torsion spring which is strained during dose setting.
 8. Theinjection device according to any of the preceding claims, wherein thegauge element (110) does not protrude out of the housing (10) duringdose setting and during dose dispensing.
 9. The injection deviceaccording to any of the preceding claims, further comprising a cartridgeholder (20) for receiving a cartridge (150), wherein the gauge element(110) is guided in the housing (10) such that the gauge element (110) atleast in one of its axial positions during dose setting overlaps atleast a part of the cartridge (150).
 10. The injection device accordingto any of the preceding claims, further comprising a piston rod (30),which is permanently rotationally constrained to the drive member (40).11. The injection device according to any of the preceding claims,comprising a limiter mechanism (64, 115; 65, 115) defining a maximumsettable dose and a minimum settable dose.
 12. The injection deviceaccording to any of the preceding claims, comprising a last doseprotection mechanism (40, 50, 60) for preventing the setting of a dose,which exceeds the amount of liquid left in a cartridge (150).
 13. Theinjection device according to any of the preceding claims, furthercomprising at least one first clicker (43, 121; 104) producing anaudible and/or tactile first feedback during dose setting and/or dosedispensing and a second clicker (105) producing an audible and/ortactile second feedback, distinct from the first feedback, during dosedispensing when the device reaches its minimum dose (zero) position. 14.The injection device according to any of claims 4 to 13, furthercomprising a second clutch (66 b, 73) rotationally coupling theactuation button (70) to the dose indicator (60) when the actuationbutton (70) and the locking element (100) are in the first dose settingposition and de-coupling the actuation button (70) from the doseindicator (60) when the actuation button (70) and the locking element(100) are in the second dose dispensing position.
 15. The injectiondevice according to any of the preceding claims further comprising acartridge (150) containing a medicament.